Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy.

Abstract:

:Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than the heart. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

journal_name

Sci Transl Med

authors

Moding EJ,Castle KD,Perez BA,Oh P,Min HD,Norris H,Ma Y,Cardona DM,Lee CL,Kirsch DG

doi

10.1126/scitranslmed.aaa4214

subject

Has Abstract

pub_date

2015-03-11 00:00:00

pages

278ra34

issue

278

eissn

1946-6234

issn

1946-6242

pii

7/278/278ra34

journal_volume

7

pub_type

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